1. BLOCKS http://www.blocks.fhcrc.org/ Multiply aligned ungapped segments corresponding to most highly conserved regions of proteins- represented in profile Built up using PROTOMAT (BLOSUM scoring model), calibrated against SWISS-PROT, use LAMA to search blocks against blocks Starting sequences from Prosite, PRINTS, Pfam, ProDom and Domo - total of 2129 families

2. Building of Blocks Alignments from Prosite Alignments from ProDom Alignments from PfamA Alignments from PRINTS Alignments from Domo Build blocks using PROTOMAT Search for common blocks LAMA- remove Build blocks using PROTOMAT Search for common blocks LAMA- remove Build blocks using PROTOMAT Search for common blocks LAMA- remove Blocks database annotated verified Unverified and changes

3. SEARCHING BLOCKS Compare a protein or DNA (1-6 frames) sequence to database of blocks Blocks Searcher- used via internet or email: First position of sequence aligned to first position of first block - score for that position, score summed over width of alignment, then block is aligned with next position etc for all blocks in database- get best alignment score. Search is slow (350 aa/2 min) Can search database of PSI-BLAST PSSMs for each blocks family using IMPALA

9. TIGRFAMs http://www.tigr.org/TIGRFAMs Collection of protein families in HMMs built with curated multiple sequence alignments and with associated functional information Equivalog- homologous proteins conserved with respect to function since last ancestor (other pattern databases concentrate on related seq not function) > 800 non-overlapping families -can search by text or sequence Has information for automatic annotation of function, weighted towards microbial genomes

10. Text search results

11. Example entry

12. Sequence search result

13. PIR-ALN http://www-nbrf.georgetown.edu/pirwww/ search/textpiraln.html Database of annotated protein sequence alignments derived automatically from PIR PSD Includes alignments at superfamily (whole sequence), family (45% identity) and domain (in more than one superfamily) levels 3983 alignments, 1480 superfamilies, 371 domains Can search by protein accession number or text

14. PROTOMAP http://www.protomap.cs.huji.ac.il Automatic classification of all SWISS-PROT proteins into groups of related proteins (also including TrEMBL now) Based on pairwise similarities Has hierarchical organisation for sub- and super-family distinctions 13 354 clusters, 5869  2 proteins, 1403  10 Keeps SP annotation eg description, keywords Can search with a sequence -classify it into existing clusters

15. DOMO http://www.infobiogen.fr/srs6bin/cgi-bin/wgetz?- page+LibInfo+-lib+DOMO (SRS) Database of gapped multiple sequence alignments from SWISS-PROT and PIR Domain boundaries inferred automatically, rather than from 3D data Has 8877 alignments, 99058 domains, and repeats Each entry is one homogous domain, has annotation on related proteins, functional families, evolutionary tree etc

16. ProClass http://pir.georgetown.edu/gfserver/proclass.html Non-redundant protein database organized by family relationships defined by ProSite patterns and PIR superfamilies. Facilitates protein family information retrieval, domain and family relationships, and classifies multi-domain proteins Contains 155,868 sequence entries

17. SBASE (Agricultural Biotechnology Centre) http://sbase.abc.hu/main.html Protein domain library from clustering of functional and structural domains SBASE entries - grouped by Standard names (SN groups) that designate various functional and structural domains of protein sequences- relies on good annotation of domains Detects subclasses too Can do similarity search with BLAST or PSI-BLAST

18. Integrating Pattern databases MetaFam IProClass CDD InterPro

19. METAFAM http://metafam.ahc.umn.edu/ Protein family classification built with Blocks+, DOMO, Pfam, PIR-ALN, PRINTS, Prosite, ProDom, SBASE, SYSTERS Automatically create supersets of overlapping families using set-theory to compare databases- reference domains covering total area Use non-redundant protein set from SPTR & PIR

20. IProClass http://pir.georgetown.edu/iproclass/ Integrated database linking ProClass, PIR-ALN, Prosite, Pfam and Blocks Contains >20000 non-redundant SP & PIR proteins, 28000 superfamilies, 2600 domains, 1300 motifs, 280 PTMs Can be searched by text or sequence

21. CDD Conserved Domain Database http://www.ncbi.nlm.nih.gov:80/Structure/cdd/cdd.shtml Database of domains derived form SMART, Pfam and contributions from NCBI (LOAD) Uses reverse position-specific BLAST (matrix) Links to proteins in Entrez and 3D structure Stand-alone version of RPS-BLAST at: ftp://ncbi.nlm.nih.gov/toolbox

22. CDD homepage

23. CDD Search result

24. DART

25. CDD example entry

26. PIR link from CDD

27. INTERPRO http://www.ebi.ac.uk/interpro Integration of different signature recognition methods (PROSITE, PRINTS, PFAM, ProDom and SMART)

28. InterPro release 3 Built from PROSITE, PRINTS, Pfam, ProDom, SMART, SWISS-PROT and TrEMBL Contains 3915 entries encoded by 7714 different regular expressions, profiles, fingerprints, Hidden Markov Models and ProDom domains InterPro provides >1 million InterPro matches hits against 532403 SWISS- PROT + TrEMBL protein sequences (68% coverage) Direct access to the underlying Oracle database A XML flatfile is available at ftp://ftp.ebi.ac.uk/pub/databases/interpro/ SRS implementation Text- and sequence-based searches

40. InterProScan PROSITE patterns: ppsearch PROSITE profiles: pfscan PFAM HMMs: hmmpfam PRINTS fingerprints: fpscan ProDom SMART eMotif derived PROSITE pattern TMHMM SignalP

42. PRINTS detailed results ANX3_MOUSE Annexin type III

43. SUMMARY Many different protein signature databases from small patterns to alignments to complex HMMs Have different strengths and weaknesses Have different database formats Therefore: best to combine methods, preferably in a database with them already merged for simple analysis with consistent format

44. Protein Secondary Structure CATH (Class, Architecture,Topology, Homology) http://www.biochem.ucl.ac.uk/dbbrowser/cath/ SCOP (structural classification of proteins) -hierarchical database of protein folds http://scop.mrc-lmb.cam.ac.uk/scop FSSP Fold classification using structure-structure alignment of proteins http://www2.ebi.ac.uk/fssp/fssp.html TOPS Cartoon representation of topology showing helices and strands http://tops.ebi.ac.uk/tops/